Type: Oral
Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Tools and Biomarkers for Improving Sickle Cell Disease Treatments
Hematology Disease Topics & Pathways:
Research, Clinical trials, Sickle Cell Disease, Clinical Research, Hemoglobinopathies, Pediatric, Diseases, Young adult , Human, Study Population
Methods: SPHERE is a prospective, phase 2 trial of open-label hydroxyurea in Tanzanian children, 2-16 years old, with SCA. All children enrolled in SPHERE with normal transcranial Doppler (TCD) velocities were initially placed into an Observation Arm, and in the SPHERE Extension trial these children were invited to begin PK-guided hydroxyurea treatment. After screening laboratory and imaging tests, a single 500mg capsule of hydroxyurea was administered as a test dose, and four serial blood samples were then collected at 15, 30, 60, and 180 minutes. Hydroxyurea serum concentrations were measured using a portable high performance liquid chromatography machine (SmartLife, PolyLC) and analyzed with our novel HdxSimTM PK model calculator to determine the dose required to achieve an area under the curve of 115 mg*h/L. If any step in the process failed, or if the calculator predicted a dose outside the normal dosing range (15-35 mg/kg/day), a default dose of 25 mg/kg/day was initiated. Doses were subsequently escalated to maximum tolerated dose (MTD) and then further optimized to maintain mild myelosuppression.
Results: Between May 2023 and May 2024, 100 children (56 females, 44 males) were enrolled at an average age of 11.4±3.8 years of age. Baseline laboratory parameters included hemoglobin (Hb) = 8.2±1.4 g/dL, mean corpuscular volume (MCV) = 84±11fL, fetal hemoglobin (HbF) = 11.4±6.4%, white blood cell count (WBC) = 10.9±3.2 x109/L, platelets = 391±146 x109/L, absolute neutrophil count (ANC) = 5.5±2.6 x109/L, and absolute reticulocyte count (ARC) = 319±104 x109/L. All 100 children had PK testing attempted with an average test dose of 20.3± 6.2 mg/kg (range 9.6-41.7 mg/kg/day). All four blood samples were successfully collected in 98 children, and laboratory measurement of serum hydroxyurea concentration was successful in 89/98 (90.8%). The hydroxyurea dose was predicted in all 89 with an average dose of 29.7±14.4 mg/kg but 20 doses were outside the expected range (17 above 35 mg/kg/day, 3 below 15 mg/kg/day). The calculated mean volume of distribution was 54.0±37.9 L/70 kg (median 47.78, IQR 41.5-52.9 L/70 kg). The mean absorption was 7.3±8.8 h-1 (median 2.7, IQR 1.2-12.5 h-1) and the mean clearance was 25.2±14.6 L/hr/70 kg (median 21.4, IQR 18.3-26.6 L/hr/70 kg).
Conclusion: This novel hydroxyurea PK-guided dosing process was successful in a majority of treatment-naïve children with SCA in Tanzania. The mean starting dose using this method was almost 30 mg/kg/day, which is higher than the typical starting dose, but very similar to the optimized doses achieved after 24 months of treatment in the original SPHERE cohort (28.7 mg/kg/day) and other prospective clinical trials in sub-Saharan Africa. PK-guided dosing with the proper laboratory and clinical support tools is feasible and could enable children to more rapidly achieve a highly effective dose of hydroxyurea with fewer monitoring labs and dose adjustments.
Disclosures: Ware: Novo Nordisk: Other: Health Equity Advisory Board; Nova Laboratories: Other: Medical Advisory Board; Merck Pharmaceuticals: Other: Medical Advisory Board; Theravia: Other: Medical Advisory Board.
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